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- PDB-6nzv: Crystal structure of HCV NS3/4A protease in complex with compound 12 -

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Basic information

Entry
Database: PDB / ID: 6nzv
TitleCrystal structure of HCV NS3/4A protease in complex with compound 12
ComponentsHCV NS3/4A protease
Keywordsviral protein/inhibitor / viral protease inhibitor / voxilaprevir / hepatitis C virus / VIRAL PROTEIN / viral protein-inhibitor complex
Function / homology
Function and homology information


host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / lipid droplet / : ...host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated suppression of host TRAF-mediated signal transduction / transformation of host cell by virus / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / lipid droplet / : / protein complex oligomerization / monoatomic ion channel activity / clathrin-dependent endocytosis of virus by host cell / viral nucleocapsid / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / induction by virus of host autophagy / ribonucleoprotein complex / viral RNA genome replication / cysteine-type endopeptidase activity / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / virion attachment to host cell / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Thrombin, subunit H - #120 / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal ...Thrombin, subunit H - #120 / Hepatitis C virus core protein, chain A superfamily / Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / Hepatitis C virus, Non-structural protein NS2 / Hepatitis C virus, Non-structural 5a protein / Hepatitis C virus, Non-structural 5a protein, domain 1a / Hepatitis C virus non-structural 5a, 1B domain / NS5A domain 1a superfamily / Hepatitis C virus non-structural 5a protein membrane anchor / Hepatitis C virus non-structural 5a zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, Core protein, C-terminal / Hepatitis C virus core protein / Hepatitis C virus, Non-structural protein E2/NS1 / Hepatitis C virus non-structural protein E2/NS1 / Hepatitis C virus, Envelope glycoprotein E1 / Hepatitis C virus envelope glycoprotein E1 / RNA dependent RNA polymerase, hepatitis C virus / Viral RNA dependent RNA polymerase / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Trypsin-like serine proteases / Thrombin, subunit H / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-L9J / Genome polyprotein
Similarity search - Component
Biological speciesHepatitis C virus subtype 1a
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsAppleby, T.C. / Taylor, J.G.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi®.
Authors: Taylor, J.G. / Zipfel, S. / Ramey, K. / Vivian, R. / Schrier, A. / Karki, K.K. / Katana, A. / Kato, D. / Kobayashi, T. / Martinez, R. / Sangi, M. / Siegel, D. / Tran, C.V. / Yang, Z.Y. / ...Authors: Taylor, J.G. / Zipfel, S. / Ramey, K. / Vivian, R. / Schrier, A. / Karki, K.K. / Katana, A. / Kato, D. / Kobayashi, T. / Martinez, R. / Sangi, M. / Siegel, D. / Tran, C.V. / Yang, Z.Y. / Zablocki, J. / Yang, C.Y. / Wang, Y. / Wang, K. / Chan, K. / Barauskas, O. / Cheng, G. / Jin, D. / Schultz, B.E. / Appleby, T. / Villasenor, A.G. / Link, J.O.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Discovery of velpatasvir (GS-5816): A potent pan-genotypic HCV NS5A inhibitor in the single-tablet regimens Vosevi®and Epclusa®.
Authors: Link, J.O. / Taylor, J.G. / Trejo-Martin, A. / Kato, D. / Katana, A.A. / Krygowski, E.S. / Yang, Z.Y. / Zipfel, S. / Cottell, J.J. / Bacon, E.M. / Tran, C.V. / Yang, C.Y. / Wang, Y. / Wang, ...Authors: Link, J.O. / Taylor, J.G. / Trejo-Martin, A. / Kato, D. / Katana, A.A. / Krygowski, E.S. / Yang, Z.Y. / Zipfel, S. / Cottell, J.J. / Bacon, E.M. / Tran, C.V. / Yang, C.Y. / Wang, Y. / Wang, K.W. / Zhao, G. / Cheng, G. / Tian, Y. / Gong, R. / Lee, Y.J. / Yu, M. / Gorman, E. / Mogalian, E. / Perry, J.K.
History
DepositionFeb 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HCV NS3/4A protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5114
Polymers21,5161
Non-polymers9943
Water2,774154
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.253, 58.959, 59.925
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein HCV NS3/4A protease


Mass: 21516.371 Da / Num. of mol.: 1 / Mutation: D168Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepatitis C virus subtype 1a / Production host: Escherichia coli (E. coli) / References: UniProt: S4UY05
#2: Chemical ChemComp-L9J / (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide


Mass: 832.953 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H54F2N6O9S
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 154 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.27 Å3/Da / Density % sol: 45.77 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 8-10% PEG 3350, 0.1M ammonium sulfate, 0.1M MES pH 6.5

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 6, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.55→50 Å / Num. obs: 151435 / % possible obs: 99.9 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.062 / Net I/σ(I): 25.05
Reflection shellResolution: 1.55→1.59 Å / Rmerge(I) obs: 0.379 / Num. measured obs: 2059

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3M5L

3m5l


Resolution: 1.55→42.028 Å / SU ML: 0.11 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 16.88
RfactorNum. reflection% reflection
Rfree0.1883 2032 6.97 %
Rwork0.1725 --
obs0.1736 29154 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.55→42.028 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1355 0 64 154 1573
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061451
X-RAY DIFFRACTIONf_angle_d0.8771995
X-RAY DIFFRACTIONf_dihedral_angle_d8.2631144
X-RAY DIFFRACTIONf_chiral_restr0.059230
X-RAY DIFFRACTIONf_plane_restr0.007249
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5478-1.58390.23781400.18911751X-RAY DIFFRACTION99
1.5839-1.62350.20631290.17521800X-RAY DIFFRACTION100
1.6235-1.66740.17161280.16221779X-RAY DIFFRACTION100
1.6674-1.71640.16121410.15671768X-RAY DIFFRACTION100
1.7164-1.77180.19671260.16281787X-RAY DIFFRACTION100
1.7718-1.83520.20361430.16071797X-RAY DIFFRACTION100
1.8352-1.90860.18091270.16491792X-RAY DIFFRACTION100
1.9086-1.99550.18541430.15571782X-RAY DIFFRACTION100
1.9955-2.10070.16671150.1561816X-RAY DIFFRACTION100
2.1007-2.23230.18351400.16871794X-RAY DIFFRACTION100
2.2323-2.40470.18881340.17441821X-RAY DIFFRACTION100
2.4047-2.64660.20011410.18181808X-RAY DIFFRACTION100
2.6466-3.02950.21491320.18121833X-RAY DIFFRACTION100
3.0295-3.81640.1711420.1761851X-RAY DIFFRACTION100
3.8164-42.04320.18711510.18041943X-RAY DIFFRACTION100

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